Mosaic Variegated Aneuploidy (MVA) is a syndrome marked by constitutional aneuploidy and features of developmental delay, seizures, and - in some cases - tumor predisposition. The tumors most frequently reported in this syndrome are Wilms tumors and rhabdomyosarcomas. While some causative mutations have been identified, many cases still do not have a genetic explanation.

Description

Whole exome sequencing (WES) of 20 families with MVA followed by targeted sequencing of TRIP13 in 12 additional children. Functional studies were done but will not be reported in this summary.

Results Summary

WES found 6 children with MVA and biallelic TRIP13 loss of function mutations. The exact mutations were the same in each child and each of these children had a Wilms tumor. Parents of these children were heterozygous for the mutation and unaffected supporting an autosomal recessive inheritance pattern. All 3 children were of Kashmiri origin and so 11 further children with Wilms tumor (but not with known MVA) whose families originated from Kashmir were sequenced - 2 of them harbored the same biallelic TRIP 13 mutation. One of these children had other syndromic features of MVA. A sixth child with MVA and a Wilms Tumor but of Norwegian origin harbored a different biallelic loss of function mutation of TRIP13.

Limitations

Whole exome sequencing does not detect non-coding mutations nor copy number alterations. It is unclear why there is some variance in the phenotype in children with the same mutation.

Bottom Line

TRIP13 mutations should be considered in children with Wilms tumors and other syndromic features such as microcephaly, developmental delay, and seizures. They should be especially considered in children of Kashmiri origin.